Clark Atlanta University, Center for Cancer Research and Therapeutic Development, 223 James P. Brawley Drive, SW, Atlanta, GA 30314, USA.
Mol Cancer Res. 2011 Jan;9(1):90-102. doi: 10.1158/1541-7786.MCR-10-0235. Epub 2010 Nov 12.
Loss of PTEN is frequently observed in androgen-independent prostate cancer, resulting in the deregulation of metastatic events. SDF1α activation of CXCR4 induces signaling pathways that have been implicated in prostate metastasis and progression to an advanced disease. The pathways of CXCR4 and PTEN converge, leading to the promotion and regulation of tumorigenesis, respectively. However, loss of PTEN may permit CXCR4 to progress prostate cancer to an advanced disease. In the present study, we investigated the involvement of PTEN in CXCR4-mediated tumorigenesis. When screening advanced metastatic prostate cancer cell lines for PTEN, we observed a loss of expression in PC3 and LNCaP cells whereas Du145 expressed wild-type PTEN. All three cell lines were positive for surface expression of CXCR4. Reconsitution of PTEN induced a mesenchymal to epithelial like morphologic change and inhibited CXCR4-mediated migration and proliferation in PC3 cells. Downregulation of PTEN by siRNA enhanced the CXCR4-mediated migratory behavior of Du145 cells. By Western blot analysis, we observed that PTEN inhibited basal AKT phosphorylation but not ERK1/2 phosphorylation in PTEN-expressing cells. Upon CXCR4 stimulation, PTEN inhibited ERK1/2 phosphorylation but not phosphorylation of AKT. The CXCR4-mediated migration of PC3 cells was through the ERK1/2 pathway, as confirmed by chemical inhibitors. On the basis of these studies, we suggest that loss of PTEN permits CXCR4-mediated functions in prostate cancer cells through the ERK1/2 pathway. Antagonizing CXCR4 and downstream signaling cascades may provide an efficient approach for treating patients with advanced prostate cancer when hormone therapy fails to the stop the growth and containment of tumors.
PTEN 的缺失在雄激素非依赖性前列腺癌中经常观察到，导致转移事件的失调。SDF1α 对 CXCR4 的激活诱导了与前列腺转移和进展为晚期疾病相关的信号通路。CXCR4 和 PTEN 的通路汇聚，分别导致肿瘤发生的促进和调节。然而，PTEN 的缺失可能允许 CXCR4 将前列腺癌进展为晚期疾病。在本研究中，我们研究了 PTEN 在 CXCR4 介导的肿瘤发生中的作用。在筛选晚期转移性前列腺癌细胞系中的 PTEN 时，我们观察到 PC3 和 LNCaP 细胞中表达缺失，而 Du145 则表达野生型 PTEN。这三种细胞系的表面均表达 CXCR4。PTEN 的重建诱导 PC3 细胞发生间质到上皮样形态变化，并抑制 CXCR4 介导的迁移和增殖。通过 siRNA 下调 PTEN 增强了 Du145 细胞中 CXCR4 介导的迁移行为。通过 Western blot 分析，我们观察到 PTEN 抑制了表达 PTEN 的细胞中 AKT 的基础磷酸化，但不抑制 ERK1/2 磷酸化。在 CXCR4 刺激下，PTEN 抑制 ERK1/2 磷酸化，但不抑制 AKT 的磷酸化。PC3 细胞的 CXCR4 介导的迁移是通过 ERK1/2 途径，这通过化学抑制剂得到证实。基于这些研究，我们认为 PTEN 的缺失允许 CXCR4 在前列腺癌细胞中通过 ERK1/2 途径发挥功能。拮抗 CXCR4 和下游信号级联可能为治疗激素治疗失败时阻止肿瘤生长和控制肿瘤的晚期前列腺癌患者提供一种有效的方法。
